CRYSTAL-STRUCTURE OF THE OBESE PROTEIN LEPTIN-E100

Mutations in the obese gene (OB) or in the gene encoding the OB recept or(OB-R) result in obesity, infertility and diabetes in a variety of m ouse phenotypes(1-7). The demonstration that OB protein (also known as leptin) can normalize body weight in ob/ob mice has generated enormou s interests(8-11). Most human obesity does not appear to result from a mutant form of leptin: rather, serum leptin concentrations are increa sed and there is an apparent inability to transport it to the central nervous system (CNS)(12). Injection of leptin into the CNS of overfed rodents resistant to peripheral administration was found to induce bio logical activity(13). Consequently, for the leptin to act as a weight- lowering hormone in human obesity, it appears that appropriate concent rations must be present in the CNS. This places a premium on understan ding the structure of the hormone in order to design more potent and s elective agonists, Here we report the crystal structure at 2.4 Angstro m resolution of a human mutant OB protein (leptin-E100) that has compa rable biological activity to wild type but which crystallizes more rea dily. The structure reveals a four-helix bundle similar to that of the long-chain helical cytokine family(14).